Clinical outcomes of Pfizer‐BioNTech COVID‐19 vaccine in children and adolescents: A systematic review

Abstract Background & Aims The BioNTech‐Pfizer vaccine is the only vaccine offered to children among all available vaccines. However, limited evidence is available about the clinical outcomes of COVID‐19 vaccines, especially among children and adolescents. This review offers a comprehensive and up‐to‐date overview of the BioNTech‐Pfizer vaccine's current information on children and adolescents. Methods The review was conducted following the PRISMA guidelines; a comprehensive search was performed in PubMed, Scopus, MEDLINE, and EMBASE databases for research publications COVID‐19 published between December 2019 and October 2021. All studies reporting on the outcomes of vaccinating children in their respective institutes were included. Results A total of 78 vaccinated children and adolescents from six studies were included. The majority of symptomatic vaccinated pediatrics were males (71%). The mean age was 15.6 years, and the BMI was 24.1. The most common clinical symptoms were found in chest pain (35%), fever (32%), and myalgia (17%). The most common cardiac symptom in the EKG results was ST elevation, and 35% of vaccinated pediatrics had elevated serum troponin. The hospitalization, including ICU admission, was lower than in unvaccinated groups. Statistically significant associations (p ≤ 0.05) were found in two symptoms (fever and headache) between the vaccinated and nonvaccinated pediatric groups. Conclusions Although we found better outcomes in the vaccinated group versus the nonvaccinated pediatric group, more studies are still crucial to further understand the specific etiology underlying postvaccination, particularly myocarditis, psychological impact, and other cardiac clinical symptoms in children and adolescents after receiving the BioNTech‐Pfizer vaccine.


| INTRODUCTION
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has swiftly spread around the world, causing a global pandemic  declared by the World Health Organization (WHO). COVID-19 resulted in a significant increase in morbidity and death, as well as significant economic damage. 1 As of November 20, 2021, there have been more than 257 million confirmed cases and more than five million death cases reported to WHO.
The highly contagious coronavirus strain has overwhelmed the global healthcare systems for the third time in this century. The first coronavirus pandemic was started in 2002 by a severe acute respiratory syndrome coronavirus (SARS-CoV-1). As a result, healthcare workers were at a higher risk of developing the disease than others in the population. 2 In 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) spread globally, causing the second outbreak. According to the WHO, the MERS-CoV virus is still circulating with a 35% fatality rate compared to 9.5% for SARS-CoV-1. 1 SARS-CoV-1 has a case fatality rate of 2%-3%, according to reports. 3 Nowadays, the world suffers from the third coronavirus infection (SARS-CoV-2) and causes severe acute respiratory syndrome. 4 In the united states (US) alone, 9%-12% of diagnosed patients with COVID-19 were children. 7 About 90% of children who tested positive were asymptomatic or had mild-to-moderate symptoms. Only 15 children required critical care in a survey of 2572 pediatric cases, with three deaths documented. 8 Another study across North America found that 18 of 48 children brought to ICUs required invasive ventilation, where 16 children survived and two died. 9 Children under the age of 1 year, as well as those with additional comorbidities or underlying diseases, were found to be at higher risk of severe illness. [10][11][12] It is suggested that COVID-19 in the pediatric population was less severe compared to cases in adults, and diagnosed children had different symptoms than adults do. 13,14 Interestingly, children might not have coughing or fever as frequently reported in adults. 14 Vaccinations and preventive measures are crucial for all ages to protect children from new variants of this virus-like Delta and Omicron and for patients with comorbidities and to have more control over disease transmission.
Accordingly, WHO granted global emergency approval of vaccines. 15 The fast development of COVID-19 vaccines raised many concerns and questions. In 2020 and during this pandemic, the messenger RNA (mRNA) type of vaccines have been used on humans and showed a significant efficacy rate. [16][17][18][19][20] The BioNTech-Pfizer COVID-19 vaccine is developed from a single-stranded mRNA made in vitro transcription from a DNA template that encodes the viral spike protein. 21 This review aims to offer healthcare workers and non-healthcare workers a comprehensive and up-to-date overview of the currently available information on the severity of the BioNTech-Pfizer vaccine in children and adolescents. Also, to provide the scientific readers with useful data that can aid in early recognition and effective prevention and management of children affected by COVID-19 and the BioNTech-Pfizer vaccine.

| METHODS
A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, 22  Given the current scarcity of evidence, preprints, in-press papers, and accepted-for-publication research were also considered.

| INCLUSION AND EXCLUSION CRITERIA
Studies were included for the systematic review if they met the following criteria (a) infants, children, and adolescents who aged <18 and had COVID-19 BioNTech-Pfizer vaccine; (b) children and adolescents who got infected with COVID-19, either confirmed microbiologically or clinically; exclusion criteria were any patient of age ≥18 years. were held until a consensus was established.

| Data extraction
We extracted as many relevant variables as possible from the information provided (age, date, etc.) and according to the main stratification variable, author, country, data source, age range, study timeframe, baseline population group, outcome (symptoms after vaccination, severity of symptoms), total sample, others. We additionally included another category of the length of stay in the hospital or ICU. We retrieved data on the age who are confirmed vaccinated by BioNTech-Pfizer COVID-19, confirmed symptoms after vaccination, and length of stay in hospitals or ICU from publicly available data. All studies included in this review were published in the United States of America (USA).

| RESULTS
The initial literature search retrieved 162 potentially relevant studies. After initial screening, one study was excluded due to duplication, and 155 studies were further excluded after reviewing the title, abstract, or not meeting the eligibility criteria.
Only six studies were relevant and included in the review ( Figure 1).

| Risk of bias assessment
Since only nonrandomized studies are included in this review, one risk of bias assessment was performed. Two researchers worked together to complete the risk of bias assessment; after that, a third researcher compared and integrated the findings of this assessment. If there was any disagreement, the fourth investigator acted as a tie-breaker. The Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool was used to perform the risk assessment.
According to the traffic light plot of the risk of bias assessment (nonrandomized studies), 81% had a low risk of bias (Table 1). Two out of six studies were found to have a moderate risk of bias. None of the studies were found to have a critical risk of bias.

| Ethical considerations
The ethical review was deemed unnecessary due to the nature of this study (a systematic review). However, all data were confidentiality observed and protected. All data used in this review were accessed and evaluated only by the researchers and kept on personal password-protected computers. The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with a unique ID: CRD42021297129.

| Study characteristics and cumulative analysis
In total, six reports were included in this study. [23][24][25][26][27][28] There were no randomized trials, and all studies were observational (retrospective, case series, and case report) as shown in Table 2 Table 3.
The symptoms of vaccinated children and adolescents were listed and summarized. The most common clinical symptoms were found in chest pain (35%), fever (32%), myalgia/muscle pain (17%), headache (8%), fatigue (13%), SOB (17%), vomiting (5%), nausea (4%), malaise (4%) and local pain (3%). The number of days to till show symptoms after administering the COVID-19 vaccine ranged from 1 to 6 days. whereas the other male patient in this study was found healthy with no medical history before receiving the vaccine. 28 Children and adolescents' clinical cardiac symptoms are also demonstrated in Table 3. It included the abnormal EKG and echocardiogram, abnormal cardiac MRI findings including pericardial effusion, and high troponin levels. It is worth noting that troponin levels were elevated in 35% of patients. 23,[25][26][27] However, no testing showed pericardial effusion.
The most common EKG result was ST elevation. Marshall et al.
found in their study that among patients who had EKG, two had RP depression, one had abnormal waves, and one had ST depression and conduction delay. 25 The abnormal echocardiogram outcomes were included in three studies. 23,26,27 For instance, Marshall et al. reported in their study that only one patient had mildly depressed RV and LV systolic function (LVEF 47%) and basal lateral and posterior strain. 23 Ejection fraction was reported by Schauer et al. 26   Pfizer performed a phase III clinical trial to study the effectiveness of their vaccine. In this study, 2260 children aged from 12 to 15 years were enrolled, only 18 cases of COVID-19 were recorded for the placebo group (n = 1129) and none were reported for the vaccinated group (n = 1131). Accordingly, the study led to FDA approval of expanding the use to children aged 12-15 years. 21 Pfizer announced that their COVID-19 vaccine will be 100% efficient in children aged 12-15. 30 This emergency use authorization by the FDA to include children 12-15 years of age was a significant step in our fight against this virus. Currently, trial studies are still ongoing to further test the vaccine's efficacy on younger children aged 6 months to 11 years. 30

| Clinical symptoms
The most common clinical symptoms of vaccinated pediatric patients were found that 27 had chest pain (35%), 25 had a fever (32%), 6 had a headache (8%), and 10 had fatigue (13%). All other symptoms are summarized in Table 3. In addition, the majority (71%) of symptomatic vaccinated pediatrics were males. The average length of hospitalization is 1-6 days. Although a number of diagnosed pediatrics with COVID-19 required ICU level care, the number of pediatrics who need ICU level care after vaccinations was only reported in one study to date. 23 Galindo et al. reported a study on the most common COVID-19 symptoms among pediatrics. 31 The authors looked up at 333 pediatric patients who were diagnosed with COVID-19 and found that fever, cough, and sore throat were listed as the most common symptoms. The signs and symptoms of the COVID-19 pediatrics were found to be noticeable to those who had the BioNTech-Pfizer vaccine. The difference between vaccinated and nonvaccinated pediatrics is summarized in Table 4. For instance, fever presented in only 32% of vaccinated pediatrics compared to 56% of nonvaccinated and diagnosed COVID-19 pediatrics. No cough symptom was reported for the vaccinated group compared to 55% for nonvaccinated pediatrics. Seventeen percent of vaccinated pediatrics had muscle pain compared to 22% of nonvaccinated pediatrics. All other signs were also found milder in the vaccinated group. Statistically significant associations (p ≤ 0.05) were found in two symptoms (fever and headache) between the vaccinated and nonvaccinated pediatric groups (Table 4). Fever and headache symptoms were found highly significant between the two groups (p ≤ 0.001).
A substantial percentage of children who were diagnosed with

| Cardiac outcomes
COVID-19 patients are commonly diagnosed with acute cardiac injury. 34 Li et al. reported that 15%-44% of COVID-19 patients had an incidence of cardiac injury, which was significantly larger than the prevalence found in congenital valvular disease (CVD) (5%-15%). 35 This complied with a study published by Guo et al., 36 which revealed that the risk of mortality from cardiac injury was substantially higher than the risk of death from pre-existing CVD. Although it was common in adults and elderly COVID-19 patients, no cases were reported for COVID-19 pediatrics. Interestingly, our findings on pediatrics who had the BioNTech-Pfizer vaccine showed that ST-segment elevation is the most common cardiac symptom in the ECG results. 14,[16][17][18] The authors analyzed all vaccinated pediatric cardiac symptoms and revealed no significant risk of mortality among patients (Table 3).
Troponin was also reported by Shi et al. as an independent risk factor and a key biomarker for a sign of death among COVID-19 patients. 37 The elevated troponin levels for vaccinated pediatrics were also measured. It indicated an increased risk of cardiac injury in children who had the BioNTech-Pfizer vaccine, but with no evidence of increased risk of mortality.

ACKNOWLEDGMENT
The publication of this article was funded by Qatar National Library.

CONFLICT OF INTEREST
The author declares no conflict of interest.
The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
All data generated during this study are included in this published article.